A Jekyll and Hyde of cytokines: IL-25 both promotes and limits inflammatory diseasesPHILADELPHIA – The same signal responsible for promoting the type of immune responses that cause asthma and allergy can also limit the type of inflammation associated with debilitating diseases like inflammatory bowel disease, arthritis and multiple sclerosis, according to researchers from the University of Pennsylvania School of Veterinary Medicine. The researchers discovered how IL-25, a signaling protein known as a cytokine, both prevents destructive inflammation and promotes immune responses associated with asthma and allergic responses.
The findings, which appear the April issue of the Journal of Experimental Medicine, suggest that manipulating IL-25 could provide a method to treat a wide variety of chronic inflammatory diseases.
"It appears that IL-25 has a Jekyll and Hyde personality: it can be helpful or hurtful depending on how it interacts with T helper cells, a subset of immune cells that influences inflammatory responses," said David Artis, an assistant professor in Penn's Department of Pathobiology and senior author of the study. "These studies show that IL-25 promotes type 2 T helper cells that drive the type of response required for eradicating worm infections and causing asthma. Importantly, IL-25 can simultaneously limit destructive inflammation caused by inflammatory T helper cells commonly found in diseases like inflammatory bowel disease, arthritis and MS."
IL-25 can be considered a "good" cytokine by limiting chronic inflammatory responses. At the same time, the ability of IL-25 to promote type 2 responses that drive asthma could be considered the "evil" side of the cytokine.
By examining mice infected with Trichuris, a species of intestinal parasites known as whipworms, the researchers were able to define IL-25's role in promoting type 2 inflammation to fight infection. In mice that lack the ability to produce IL-25, researchers saw a dramatic reduction in the ability to mount a type 2 response that eradicates the parasites. Furthermore, in the absence of IL-25, mice developed a destructive inflammatory response similar to that observed in models of inflammatory bowel disease.
These results also support the notion that the immune response that causes allergies and asthma is an evolutionary hangover resulting from mankind's historical fight with parasitic worm infections. That is, a type 2 response that was once useful in fighting worm infections has now become a dangerous menace, causing inflammatory responses to commonly encountered environmental antigens. About 30 percent of Americans suffer from the negative affects of type 2 inflammation: asthma and allergies. These conditions result from an inflammatory response to factors encountered in the environment, whether they are industrial air pollutants or molecules of peanut oil.
"It is possible that for most of human history, cytokines like IL-25 have promoted type 2 T helper cells that fight infection with intestinal parasites like Trichuris, " said Colby Zaph, a co-author and Irvington Research Fellow at Penn. "In industrialized countries, where worm infections are now rare, this redundant type 2 response is associated with diseases like asthma. "Identifying a role for IL-25 in this type of response may offer an exciting new avenue for treating diseases associated with dysregulated inflammatory responses," Zaph said.
Researchers involved in this report include Colby Zaph, Emma H. Wilson, Katherine J. Guild, Christopher A. Hunter and David Artis from Penn; Hugh R. P. Miller from the University of Edinburgh; and Alexander M. Owyang, Terrill McClanahan, Daniel J. Cua and Robert A. Kastelein from Schering-Plough Biopharma.
Funding for this research was provided by the National Institutes of Health, The Crohn's and Colitis Foundation of America's William Shelby Modell Family Foundation Research Award, the Irvington Institute for Immunological Research and Schering-Plough Biopharma.
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